Recent clinical trials have shown that antiestrogens can reduce the risk of invasive breast cancer in high-risk women without existing cancer. However, antiestrogens do not reduce the incidence of estrogen (ER) receptor negative breast cancers in these women. Thus, there is an urgent need to identify and test agents that will prevent the development of ER-negative breast cancer. While ER-negative breast cells do not respond to estrogen, many do require growth factors such as EGF, TGFbeta, and IGF-I, so that inhibitors of signal transduction from these growth factors could be preventioncandidates. A particularly promising agent is Iressa, which inhibits the tyrosine kinase activity of the EGF receptor.This drug suppresses the growth of many cancer cells in vitro, including breast cancer cells. Phase I and II clinical trials of Iressa to treat cancer have shown dramatic responses, and have also shown that Iressa is well tolerated with minimal toxicity. Our preliminary studies demonstrate that Iressa blocks signal transduction and inhibits growth in normal as well as malignant breast tissue, and suppresses the formation of mammary tumors in transgenic mice. We now propose three Aims testing the hypothesis that Iressa will prevent the development of ER-negative as well as ER-positive breast cancer in animals, and will inhibit signal transduction and suppress breast cell proliferation in humans. 1) Does Iressa prevent ER-negative breast cancer induced by activation of peptide growth factor receptors? We will treat both MMTV-TGFalpha and MMTV-erbB2 transgenic mice with lressa or vehicle, compare the time to tumor formation, tumor multiplicity, and tumor growth rate, and investigate how Iressa affects proliferation, apoptosis, and activation of downstream signaling intermediates in mammary tissue. 2) Does Iressa prevent both ER-positive and ER-negative breast cancers arising in P53-null mammar,glands? We will use mice receiving mammary gland transplants from P53 null mice--the mammary tmnors that develop are approximately 20% ER-positive and 80% ER-negative--to determine whether Iressa suppresses both tumor types, and whether the combination of Iressa plus tamoxifen suppresses tumor development more effectively than either treatment alone. 3) Does Iressa inhibit signal transduction and suppress breast cell proliferation in women at high risk of breast cancer? We will conduct a Phase I/II chemoprevention trial in high-risk women, determining whether Iressa decreases markers of proliferation and activated signal transduetion in breast epithelial cells obtained by core needle biopsy, and comparing two doses of Iressa for their effectiveness as well as their safety profile and toxicity in these women. These studies will provide the preelinical and clinical foundation to develop tyrosine kinase inhibitors as cancer preventive agents in future Phase III breast cancer prevention trials.